vitamin-k-semiquinone-radical and fluindione

Except for bleeding complications, vitamin K antagonists (VKAs) are known to have few undesirable side effects. Herein is presented the case of a 45-year-old woman in whom liver damage was induced by fluindione and warfarin after mitral valve replacement. Hepatotoxicity is a rare complication of VKAs, both in the French National and Drug Safety registry and the medical literature. A diagnosis of VKA-induced drug damage was confirmed by the absence of other etiologies, the chronological sequence, recurrence after re-exposure to VKA, and rapid improvements after discontinuation of the drug. Despite possible cross-reactions between VKAs, the re-introduction of acenocoumarol was successfully achieved, with no recurrence of biological disturbances.

Topics: Anticoagulants; Chemical and Drug Induced Liver Injury; Drug Substitution; Female; Fibrinolytic Agents; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Heparin, Low-Molecular-Weight; Humans; Liver Function Tests; Middle Aged; Mitral Valve; Phenindione; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

The purpose of this review article is to summarize the literature on diseases that are documented to have an effect on response to warfarin and other VKAs.. We searched the English literature from 1946 to September 2015 via PubMed, EMBASE, and Scopus for the effect of diseases on response vitamin K antagonists including warfarin, acenocoumarol, phenprocoumon, and fluindione.. Among many factors modifying response to VKAs, several disease states are clinically relevant. Liver disease, hyperthyroidism, and CKD are well documented to increase response to VKAs. Decompensated heart failure, fever, and diarrhea may also elevate response to VKAs, but more study is needed. Hypothyroidism is associated with decreased effect of VKAs, and obese patients will likely require higher initial doses of VKAs.. In order to minimize risks with VKAs while ensuring efficacy, clinicians must be aware of the effect of disease states when prescribing these oral anticoagulants.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Cardiovascular Diseases; Diarrhea; Fibrinolytic Agents; Heart Failure; Humans; Hyperthyroidism; Kidney Failure, Chronic; Liver Diseases; Obesity; Phenindione; Phenprocoumon; Vitamin K; Warfarin

Numerous factors are well documented to affect the response to vitamin K antagonists (VKA), including dietary vitamin K, other drugs, age, pharmacogenetics, and disease states. Body weight is perhaps not as well known as a variable affecting VKA dose. Our aim was to review the literature regarding body weight and VKA dose requirements.. We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight.. Among 32 studies conducted since the widespread use of the international normalized ratio, 29 found a correlation with body weight or body surface area and VKA dose requirement. Warfarin was evaluated in 27 studies and acenocoumarol, phenprocoumon, or fluindione were assessed in 5 investigations.. Because of varying study methodologies, further study is warranted. Based on current evidence, clinicians should include body weight, along with other established variables when dosing VKA. Most important, obese and morbidly obese patients may require a 30% to 50% increase with the initial dosing of VKA.

Topics: Acenocoumarol; Anticoagulants; Body Weight; Comorbidity; Drug Dosage Calculations; Humans; Obesity; Obesity, Morbid; Phenindione; Phenprocoumon; Vitamin K; Warfarin

To evaluate the therapeutic impact of an education program on patients undergoing oral anticoagulation treatment, within the hospital of Annecy (France).. Groups of 10 patients were invited to participate to two meetings. The education was carried out by two nurses. Thanks to this prospective study, we compare the population before and after education in terms of treatment knowledge and stability.. Within 9 months 88 patients have been included, amongst which 55 have attended the two meetings. The average of correct answers to the knowledge evaluation questionnaire distributed before and after 6 months of education were, respectively, 6.63/12, 10.09/12 (P < 0.0001). Through INR controls within the 6 months preceding (424 controls) and the 6 months following the education (619 controls), we observe: an increase of the total INR average in therapeutic zone, from 45% to 61% (P < 0.0001); a decrease of the difference average per patient between the INR value observed and the one targeted: 0.54 before education, 0.40 after education (P = 0.0016); at last, the average phasing per patient under the therapeutic zone increases after education, from 49% to 65% (P < 0.001).. The education improves objectively the knowledge of patient undergoing AVK. If the size of patient sample is not large enough to prove any consequence on hemorrhagic or thrombotic complications, the education program still improves significantly the treatment stability.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Chi-Square Distribution; Data Interpretation, Statistical; Female; Heart Diseases; Humans; Male; Middle Aged; Patient Education as Topic; Patient Satisfaction; Phenindione; Surveys and Questionnaires; Thromboembolism; Time Factors; Vitamin K

Vitamin K antagonists (VKA) decrease the synthesis of the active forms of four coagulation factors (factors II, VII, IX, X) and three inhibitors (proteins C, S, Z). There are VKA having a short half life (Sintrom, Pindione) and VKA having a long half life (Apegmone, Previscan, Coumadine). The treatment is monitored by the INR which in the majority of the indications must range between two and three. The first INR is usually performed 36 to 72 h after starting the treatment. There are a number of drug interactions. The rate of major bleedings range from 1.1 to 4.9 for 100 patient-year according to the published studies. Since around 600,000 patients are treated by VKA in our country, the absolute number of serious bleeding is high (> or = 17,000 per year). Anticoagulant clinics are structures aimed to instruct the patient and to advise the general practitioner to monitor the treatment, using computer assisted methods. It has been reported that these structures reduce the incidence of bleeding and of thrombotic events by 3 to 4 times.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Drug Interactions; Family Practice; Food; Hemorrhage; Humans; Patient Education as Topic; Phenindione; Thrombosis; Time Factors; Vitamin K; Warfarin

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.. 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.. 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).. 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.).

Topics: 4-Hydroxycoumarins; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Mortality; Phenindione; Postoperative Complications; Pyridines; Thiazoles; Thromboembolism; Transcatheter Aortic Valve Replacement; Vitamin K

Reversal of overanticoagulation to minimize the bleeding risk is important in elderly inpatients receiving vitamin K antagonist therapy. However, no study has specifically focused on this population. The objective of this study is to evaluate whether guidelines based on American College of Chest Physicians recommendations for the management of overanticoagulation (international normalized ratio [INR] ≥5.0) can apply to elderly inpatients, and notably allow 24-hour INRs to return to the 1.8-3.2 range in this population. The influence of different factors on the vitamin K response also was evaluated.. Inpatients aged ≥75 years with INR ≥5.0 were included in this observational study. INRs were assessed on the day of the overdosage (Day 0) and on the following day (Day 1).. Of 385 Day 0 INRs ≥5.0 (239 patients; 86±6 years), 217 were managed according to recommendations, with a mean INR decreasing from 6.8±2.4 (range: 5.0-20.0) on Day 0 to 2.7±1.3 (range: 1.1-10.1) on Day 1 (P<.0001); 55% of INRs were within the 1.8-3.2 range, 20% <1.8, and 25% >3.2. In the subset of Day 0 INRs between 5.0 and 6.0, mean INR decreased from 5.5±0.3 to 2.7±1.0 (P<.0001) on Day 1 after oral administration of 1 mg vitamin K1 (n=121) and from 5.3±0.3 to 5.0±1.6 (P=.149) without vitamin K1 administration (n=48). Among covariates entered in the multivariate analysis, including co-medications, only the vitamin K1 dose influenced Day 1 INRs, with higher doses of vitamin K1 associated with Day 1 INRs <1.8 (P<.0001).. In elderly inpatients with INR ≥5.0, both vitamin K antagonist dose omission and vitamin K1 administration according to recommendations were effective in reversing overanticoagulation, allowing most INRs to return to the 1.8-3.2 range without excessive overcorrection. Therefore, American College of Chest Physicians recommendations may be applied to elderly inpatients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Drug Administration Schedule; Drug Interactions; Female; Hemorrhage; Hospitals, Teaching; Humans; Inpatients; International Normalized Ratio; Male; Multivariate Analysis; Paris; Phenindione; Time Factors; Vitamin K; Warfarin

Thrombin is a main mediator of arterial thrombus formation, and its inhibition is an important antithrombotic strategy. However, the place of vitamin K antagonists among the different therapeutic strategies for preventing arterial thrombus formation is still debated. We studied the antithrombotic efficacy of the vitamin K antagonist fluindione in a human ex vivo model of arterial thrombosis and determined whether aspirin enhances fluindione efficacy. Ten healthy male volunteers were randomly assigned to receive fluindione, alone or in combination with aspirin (325 mg/d). Fluindione was given at increasing doses to give a stable international normalized ratio (INR) between 1.5 and 2.0 and between 2.1 and 3.0. We induced arterial thrombus formation ex vivo by exposing collagen- or tissue factor (TF)-coated coverslips in a parallel-plate perfusion chamber to native blood for 3 minutes at an arterial wall shear rate of 2600 s(-1). Platelet and fibrin deposition were measured by immunoenzymatic methods. Fluindione inhibited thrombus formation on TF-coated coverslips in a dose-dependent manner by 50% and 80% at INR 1.5 to 2.0 and INR 2.1 to 3.0, respectively (P<0.05). Fluindione in combination with aspirin inhibited TF-induced thrombus formation in a comparable manner. Collagen-induced thrombus formation was not reduced in subjects treated by fluindione. It was reduced by 50% to 60% in those treated with fluindione plus aspirin, regardless of the level of anticoagulation (P<0.05). Thus, the effectiveness of fluindione for preventing arterial thrombosis is dependent on the nature of the thrombogenic trigger. Fluindione is very effective in preventing TF- but not collagen-triggered thrombus formation. Aspirin enhances the antithrombotic effectiveness of fluindione, because combined treatment interrupts both TF- and collagen-induced thrombus formation.

Topics: Adolescent; Adult; Anticoagulants; Aspirin; Collagen; Drug Synergism; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Male; Phenindione; Thromboplastin; Thrombosis; Vitamin K

Topics: 4-Hydroxycoumarins; Aged, 80 and over; Allopurinol; Anticoagulants; Drug Interactions; Drug Overdose; Humans; Iatrogenic Disease; Indenes; Macular Degeneration; Male; Phenindione; Retinal Detachment; Retinal Hemorrhage; Vitamin K

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Tests; Factor X; Female; Humans; Male; Middle Aged; Phenindione; Prothrombin; Reference Values; Vitamin K; Warfarin

Essentials Acute coronary syndrome (ACS) with atrial fibrillation (AF) is a therapeutic challenge. Dual and triple antithrombotic therapy showed a similar thrombotic risk in ACS patients with AF. The omission of aspirin during the first month did not increase the rate of ischemic events. Replacement of vitamin K antagonist by dabigatran leads to an increased thrombotic risk.. Background Dual antithrombotic therapy comprising a vitamin K antagonist (VKA) plus clopidogrel reduces the incidence of major bleeding compared with triple therapy (VKA + clopidogrel + aspirin) in acute coronary syndrome (ACS) patients with atrial fibrillation (AF), with a similar thrombotic risk. The oral thrombin inhibitor dabigatran (150 mg twice a day) showed superiority over VKA in non-valvular AF, but data supporting its use in AF patients presenting with ACS are limited. Objective We sought to evaluate the efficacy of dabigatran vs. VKA in the management of AF patients undergoing percutaneous coronary intervention for an ACS. Methods In this open-label study, 133 consecutive patients received dabigatran plus clopidogrel. Another cohort of 133 patients treated with VKA plus clopidogrel was used as the control group. Results After propensity score adjustment, the cumulative incidence of major adverse cardiovascular events over 24 months was higher with dabigatran vs. VKA (adjusted hazard ratio, 2.28; 95% confidence interval, 1.46-3.56). Similar rates of major bleeding were found (adjusted hazard ratio, 1.17; 95% confidence interval, 0.46-2.96). Conclusions In AF patients presenting with ACS, replacement of VKA by dabigatran concurrently with clopidogrel is associated with an increased thrombotic risk, without a reduction in major bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Blood Platelets; Clopidogrel; Cohort Studies; Coronary Angiography; Dabigatran; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Incidence; Ischemia; Kaplan-Meier Estimate; Male; Middle Aged; Outcome Assessment, Health Care; Patient Safety; Phenindione; Propensity Score; Proportional Hazards Models; Risk; Treatment Outcome; Vitamin K

Isolated arthralgia, without hemorrhagic side effect, exists and is considered as a very rare adverse drug reaction according to vitamin K antagonists' (VKAs) summary of product characteristics. Up to now, there are no literature reports of isolated, nonhemorrhagic joint complications in patients receiving VKAs. Hence, the objective of this study was to describe cases of VKA-related nonhemorrhagic joint disorders (fluindione, warfarin, and acenocoumarol) reported in the French Pharmacovigilance Database (FPVD). Sixty-one reports (male : female ratio, 1.18; median [interquartile range (IQR)] age: 60 [49-72]) were found. Fluindione, warfarin, and acenocoumarol were respectively suspected in 42, 12, and 7 cases. Arthralgia was reported in 47 cases (77%), arthritis in nine cases (15%), capsulitis in three cases (5%), and bursitis in two cases (3%). Although the joint symptoms mainly concerned the lower limbs, all types of joints were affected. Arthralgia was associated with myalgia in 14 cases and with tendinitis in three cases. The median (IQR) time interval between VKA introduction and arthralgia onset was 26 (10-98) days (range: 1-6935). VKA was withdrawn in 44 cases, and a decrease in the intensity of joint symptoms was observed in 30 cases. In three cases, reintroduction of the same VKA led to the recurrence of symptoms. In view of the large prescription of this drug class worldwide, patients and clinicians (and especially primary care physicians and geriatricians) should be aware of this possible adverse drug reaction when confronted with joint disorders in patients of all ages taking VKAs.

Topics: Acenocoumarol; Aged; Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Joint Diseases; Male; Middle Aged; Pharmacovigilance; Phenindione; Vitamin K; Warfarin

Despite the increasing utilization of direct oral anticoagulant (DOAC) prescriptions, vitamin K antagonists (VKAs) remain the treatment of choice for treating and preventing thromboembolic events. The morbidity and mortality of VKAs are partly due to the difficulty of keeping the patient within the therapeutic range. For patients treated by VKA, time in therapeutic range (TTR) is a quality parameter of treatment, widely used in clinical trials but rarely by prescribers. It is well established that its use correlates with the risk of hemorrhage, thrombosis or mortality. We studied this parameter in a cohort of patients to evaluate the quality of their therapeutic follow-up and tried to identify risk factors for low TTR.. The study was made in collaboration with LaboSud Oc Biologie for a duration of 4 months. It included 3387 patients representing 2,4029 INR. We calculated the patients' TTR. The laboratory transmitted to us the sex and age of each patient and the VKA molecule used, the therapeutic range and the specialty of the prescriber. We then analyzed the odds ratio associated with these different factors.. The mean TTR was 68%, close to the TTR recommended by scientific societies. Patient's sex was the only statistically correlated factor, with a worse equilibrium in females taking VKAs (OR=1.22, 95% CI: 1.06-1.39, P=0.00552). Many factors usually correlated with poor equilibrium under VKA have not been studied due to lack of information.. Given the context of economic restriction and the TTR of our cohort close to the recommended 70%, there would be no benefit in terms of safety to prefer DOAC for the patients involved in this study. Regular monitoring of the individual patient's as well as the cohort's TTR should optimize the management of patients receiving VKAs.

Topics: Acenocoumarol; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Phenindione; Risk Factors; Sex Factors; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These anticoagulants function by impairing the biosynthesis of active vitamin K-dependent coagulation factors through the inhibition of vitamin K epoxide reductase (VKOR). Genetic variations in VKOR have been closely associated with the resistant phenotype of oral anticoagulation therapy. However, the relative efficacy of these anticoagulants, their mechanisms of action, and their resistance variations among naturally occurring VKOR mutations remain elusive. Here, we explored these questions using our recently established cell-based VKOR activity assay with the endogenous VKOR function ablated. Our results show that the efficacy of these anticoagulants on VKOR inactivation, from most to least, is: acenocoumarol > phenprocoumon > warfarin > fluindione. This is consistent with their effective clinical dosages for stable anticoagulation control. Cell-based functional studies of how each of the 27 naturally occurring VKOR mutations responds to these 4 oral anticoagulants indicate that phenprocoumon has the largest resistance variation (up to 199-fold), whereas the resistance of acenocoumarol varies the least (<14-fold). Cell-based kinetics studies show that fluindione appears to be a competitive inhibitor of VKOR, whereas warfarin is likely to be a mixed-type inhibitor of VKOR. The anticoagulation effect of these oral anticoagulants can be reversed by the administration of a high dose of vitamin K, apparently due to the existence of a different enzyme that can directly reduce vitamin K. These findings provide new insights into the selection of oral anticoagulants, their effective dosage management, and their mechanisms of anticoagulation.

Topics: Administration, Oral; Anticoagulants; Cell Line; Drug Resistance; Enzyme Inhibitors; Humans; Phenindione; Point Mutation; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

Skin necrosis with vitamin k antagonists are rare. They affect more frequently middle-aged and obese women, often within 10 days after initiating of treatment. They occur most often in a context of thrombophilia.. An 18-year-old obese woman was treated with heparin and fluindione for a lower limb deep venous thrombosis. On day 5, the patient presented fever and skin necrosis, which extended rapidly. We identified an activated protein C resistance and a major inflammatory syndrome related to Mycoplasma pneumoniae infection. The outcome was favorable after discontinuation of the fluindione, introduction of heparin and vitamin K, despite amputation of a toe.. Skin necrosis is due to a transient hypercoagulable state during the initiation of vitamin K antagonist treatment due to an imbalance between pro- and anticoagulant factors. In our case, it was caused by an activated protein C resistance and an inflammatory syndrome.

Topics: 4-Hydroxycoumarins; Adolescent; Amputation, Surgical; Anticoagulants; Breast; Coagulants; Female; Hallux; Heparin; Humans; Indenes; Necrosis; Phenindione; Skin; Vitamin K

Spontaneous hematoma of transverse mesocolon is a rare complication of anticoagulant treatment with vitamin K. We report the case of spontaneous hematoma of right angle of the transverse mesocolon associated with a hemoperitoneum in a 32-year-old patient treated by fluindione for pulmonary embolism. The diagnosis must be made urgently. The abdominal ultrasound and the scanning confirm the diagnosis. It is important to note that surgery is indicated only in the case of complications such as the risk of rupture of the hematoma.

Topics: Adult; Anticoagulants; Female; Hematoma; Hemoperitoneum; Humans; Mesocolon; Phenindione; Pulmonary Embolism; Vitamin K

Vitamin K is involved in brain physiology, suggesting that its deficiency induces cognitive decline. Our objective was to determine whether using vitamin K antagonists (VKAs) was associated with cognitive impairment among geriatric patients.. Two hundred sixty-seven older patients (mean, 83.4 ± 8.1 years; 56.9% female) were categorized according to cognitive impairment (ie, Mini-Mental State Examination ≤ 25). The regular use of VKAs was sought by questioning the patients, relatives, and family physicians. Age, gender, body mass index, comorbidity burden, mood and executive functioning, history of atrial fibrillation, ischemic stroke, intracranial hemorrhage and transient ischemic attack, use of other anticoagulants and antiplatelet medications, and severe renal failure were used as potential confounders.. Compared with participants without cognitive impairment (n = 70), those with Mini-Mental State Examination ≤ 25 used more frequently VKAs (p = .038). The risk of cognitive impairment was 15% higher with VKAs, specifically with fluindione. Using VKAs was independently associated with cognitive impairment (fully adjusted odds ratio = 17.4 [95% CI: 1.4-224.2], p = .028).. We found more frequent cognitive impairment associated with the use of VKAs, specifically fluindione, among geriatric patients.

Topics: Aged; Aged, 80 and over; Aging; Anticoagulants; Atrial Fibrillation; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Male; Mental Status Schedule; Phenindione; Pilot Projects; Risk Factors; Stroke; Vitamin K

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Electrocardiography; Factor Xa Inhibitors; Female; Humans; Phenindione; Rivaroxaban; Thrombosis; Vitamin K

Patients with non-valvular atrial fibrillation who are receiving or have been previously exposed to a vitamin K antagonist could be switched to a non-vitamin K-antagonist oral anticoagulant (NOAC) but little information is available about the risk of bleeding and arterial thromboembolism after such a switch. We aimed to compare the risk of bleeding between individuals who switched and those who remained on a vitamin K antagonist (non-switchers) in real-world conditions.. We did a matched-cohort study with information from French health-care databases. We extracted data for adults (aged ≥18 years) with non-valvular atrial fibrillation who received their first prescription for a vitamin K antagonist (fluindione, warfarin, or acenocoumarol) between Jan 1, 2011, and Nov 30, 2012, and who were either switched to a NOAC (dabigatran or rivaroxaban) or maintained on the vitamin K antagonist. Each switcher was matched with up to two non-switchers on the basis of eight variables, including sex, age, and international normalised ratio number. The primary endpoint was incidence of bleeding (intracranial haemorrhage, gastrointestinal haemorrhage, or other) in switchers versus non-switchers, and switchers stratified by type of NOAC versus non-switchers, noted from databases of hospital admissions. Each patient was followed up to 1 year; the study closed on Oct 1, 2013.. Of 17,410 participants, 6705 switched to a NOAC (switchers) and 10,705 remained on vitamin K-antagonist therapy (non-switchers). Median age of participants was 75 years (IQR 67-82), 8339 (48%) were women, and the median duration of vitamin K-antagonist exposure before a switch was 8.1 months (IQR 3.9-14.0). After a median follow-up of 10.0 months (IQR 9.8-10.0), we noted no difference between groups for bleeding events (99 [1%] in switchers vs 193 [2%] in non-switchers, p=0.54). In adjusted multivariate analyses, the risk of bleeding in switchers was not different from that in non-switchers (hazard ratio [HR] 0.87; 95% CI 0.67-1.13, p=0.30). Additionally, no differences were noted when the risk of bleeding was compared between switchers from a vitamin K antagonist to dabigatran (HR 0.78, 95% CI 0.54-1.09, p=0.15), switchers from a vitamin K antagonist to rivaroxaban (HR 1.04, 95% CI 0.68-1.58, p=0.86), and non-switchers.. In this matched-cohort study, our findings suggest that patients with non-valvular atrial fibrillation who switch their oral anticoagulant treatment from a vitamin K antagonist to a non-vitamin K antagonist are not at increased risk of bleeding. Future studies with longer follow-up might be needed.. None.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Phenindione; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Thromboembolism; Vitamin K; Warfarin

Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0-3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

Topics: Aged; Aged, 80 and over; Amiodarone; Body Weight; Drug Dosage Calculations; Female; Gene-Environment Interaction; Genotype; Heart Rate; Humans; Inactivation, Metabolic; Male; Models, Biological; Pharmacogenetics; Phenindione; Polymorphism, Genetic; Vascular Resistance; Vitamin K

Due to improved implementation of guidelines, new scoring approaches to improve risk categorisation, and introduction of novel oral anticoagulants, medical management of patients with atrial fibrillation (AF) is continuously improving. The PREFER in AF registry enrolled 7,243 consecutive patients with ECG-confirmed AF in seven European countries in 2012-2013 (mean age: 71.5 ± 10.7 years; 60.1% males; mean CHA2DS2-VASc score: 3.4). While patient characteristics were generally homogeneous across countries, anticoagulation management showed important differences: the proportion of patients taking vitamin K antagonists (VKAs) varied between 86.0% (in France) and 71.4% (in Italy). Warfarin was used predominantly in the UK and Italy (74.9% and 62.0%, respectively), phenprocoumon in Germany (74.1%), acenocoumarol in Spain (67.3%), and fluindione in France (61.8 %). The major sites for international normalised ratio (INR) measurements were biology laboratories in France, anticoagulation clinics in Italy, Spain, and the UK, and physicians' offices or self-measurement in Germany. Temporary VKA discontinuation and bridging with other anticoagulants was frequent (at least once in the previous 12 months for 22.9% of the patients, on average; ranging from 29.7% in Germany to 14.9% in the UK). Time in therapeutic range (TTR), defined as at least two of the last three available INR values between 2.0-3.0 prior to enrolment, ranged from 70.3% in Spain to 81.4% in Germany. TTR was constantly overestimated by physicians. While the type and half-lives of VKA as well as the mode of INR surveillance differed, overall quality of anticoagulation management by TTR was relatively homogenous in AF patients across countries.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Europe; Female; Humans; Male; Middle Aged; Phenindione; Phenprocoumon; Practice Guidelines as Topic; Registries; Vitamin K; Warfarin; Withholding Treatment

To identify, in a case-control study, the risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists.. We performed a single-centre observational study during a three-month period where we consecutively included patients admitted to the emergency department of a secondary-level hospital and treated with vitamin K antagonists, regardless the reason for admission. Patients admitted for a thrombotic or bleeding event were included as cases and the other patients served as controls. Main thrombotic or bleeding risk factors during vitamin K antagonist therapy were a priori identified in literature and tested in conditional logistic regression.. Two hundred and forty subjects were identified, 40 of which (17%) were admitted for a bleeding event, 19 (8%) for a thrombotic event and 181 (75%) for another reason. Over 85% of patients were treated with fluindione. No risk factor was significantly associated with bleeding or thrombotic event in patients treated with vitamin K antagonist. Patients presenting a thrombotic event were however more likely to have a chronic respiratory disease.. In this study, no risk factor significantly associated with a bleeding or thrombotic event in patients treated with vitamin K antagonist were identified. The occurrence of these events supposes other risk factors, including potential genetic polymorphisms that should be considered in future studies.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Drug Interactions; Emergency Service, Hospital; Female; Genetic Predisposition to Disease; Hemorrhage; Humans; International Normalized Ratio; Male; Phenindione; Respiration Disorders; Risk Factors; Secondary Care Centers; Thrombosis; Vitamin K; Warfarin

Topics: Aged; Anticoagulants; Antitubercular Agents; Comorbidity; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Interstitial; Pericarditis; Phenindione; Polypharmacy; Postoperative Complications; Rifampin; Sirolimus; Venous Thrombosis; Vitamin K

Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics.. We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000.. Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases.. Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment.

Topics: Administration, Oral; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Anticoagulants; Drug Eruptions; Drug Hypersensitivity; Eosinophilia; Female; France; Humans; Male; Middle Aged; Pharmacovigilance; Phenindione; Retrospective Studies; Severity of Illness Index; Skin Tests; Vitamin K

Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis.. Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA.. The subjects studied included 20 men and 4 women, with a mean age of 73.0±9.3 years (range: 44-84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9±6.9 weeks (range: 3-28). Creatinine increased from 123.0±56.4 μmol/L (range: 56-335) at fluindione introduction to 460.7±265.3 μmol/L (range: 109-1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4-5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione.. In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anticoagulants; Coumarins; Drug Hypersensitivity; Female; Follow-Up Studies; France; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Phenindione; Prognosis; Retrospective Studies; Vitamin K

Vitamin K antagonists (VKAs) are widely used in thromboembolic diseases. We report five cases of necrotic leg ulcers having a particularly severe course and in which withdrawal of VKA treatment alone enabled healing.. Five patients presented with necrotic leg ulcers clinically evocative of necrotic angiodermatitis or vasculitis. Histological features were variable, including inconstantly inflammatory lesions (leukocytoclastic vasculitis) and microthrombosis. None of the patients had laboratory signs of autoimmune disease. Healing occurred in all patients only after withdrawal of VKA therapy (fluindione or acenocoumarol). Associated vascular diseases included superficial venous, distal arterial insufficiency and postphlebitic disease. In three cases, thrombotic factors were observed: hyperhomocysteinaemia or heterozygous Factor V Leiden mutation.. Although the causative role of VKAs is based solely on chronological criteria, this potential side effect deserves publication because of its practical therapeutic consequences. The physiopathological mechanisms accounting for the role of VKAs, including immunoallergic phenomena and, above all, microcirculatory thrombotic processes, are hypothetical and not universally accepted.

Topics: Acenocoumarol; Activated Protein C Resistance; Aged; Aged, 80 and over; Anticoagulants; Diabetic Angiopathies; Factor V; Female; Humans; Hyperhomocysteinemia; Leg Ulcer; Male; Necrosis; Phenindione; Polyarteritis Nodosa; Postoperative Complications; Purpura; Thrombophilia; Varicose Ulcer; Vasculitis, Leukocytoclastic, Cutaneous; Vitamin K

Topics: Anticoagulants; Drug Interactions; Female; HIV Seropositivity; Humans; Middle Aged; Nevirapine; Phenindione; Treatment Failure; Vitamin K; Warfarin

Vitamin K antagonists (VKA) are very currently used. Nevertheless, they are known to interact with numerous drugs and foods. Grapefruit juice is known to interact with some drugs metabolized by the enterocytary cytochrome P450 3A4 but its interaction with drugs as VKA that have a good biodisponibility is not clearly demonstrated. We report here the case of a woman treated with VKA in whom massive absorption of grapefruit juice entailed an excessive VKA dosage and a severe haemorrhage.

Topics: Absorption; Anticoagulants; Beverages; Citrus paradisi; Drug Overdose; Female; Food-Drug Interactions; Humans; Middle Aged; Phenindione; Severity of Illness Index; Vitamin K

The primary aim of this study was to analyze the quality of oral anticoagulation management in the real-life practice of hospital geriatric departments, in the absence of a formal dose-adjustment protocol. The secondary objective was to identify factors associated with international normalized ratios (INR) outside the target range.. This prospective study was conducted between November 2004 and August 2005 in our hospital's acute geriatric care and geriatric rehabilitation units. It included 110 subjects older than 65 years, all taking fluindione (target INR range of 2 to 3). Indications for oral anticoagulation were atrial fibrillation, venous thromboembolism, and pulmonary embolism. Patients were eligible for inclusion if they had at least 4 INR measurements, and we assessed a maximum of 20 such measures per patient.. The study included 74 patients in the acute geriatric unit and 36 subjects in rehabilitation units (mean age: 85 years [65-97 years]), who had 1079 INR tests during the study period (mean per patient: 9.8 (+/-5.5)). Overall, 333 patients (31%) were in the target range of 2-3, 48% below 2, 21% above 3, and 3.6% above 5. The time interval between INR tests did not vary when INR was below 2, but we noted a nonsignificant trend towards a reduction in the average testing interval when INR was above 3 (p=0.079). No bleeding or thrombotic complications were reported during the study. Of the 11 predefined variables, only cancer (history or current) was significantly associated with elevated INR.. This study confirms the difficulty of controlling INR in anticoagulation therapy of elderly subjects. Only 31% of tests showed INR in the target range of 2 to 3, a rate lower than in other cohorts. These results may be explained by the high rate of comorbidities in this very old study population.

Topics: Aged; Aged, 80 and over; Anticoagulants; Female; Follow-Up Studies; Hospitalization; Humans; Male; Phenindione; Prospective Studies; Risk Factors; Vitamin K

Acute interstitial nephritis is a frequent cause of acute renal failure, representing about 10% of all biopsied cases. Early recognition of drug-induced acute immunoallergic interstitial nephritis prevents the development of severe chronic renal injury. The list of imputable drugs includes phenindione, a vitamin K antagonist. Fluindione which is also an indanedione derivative is another vitamin K antagonist. We report three biopsy-proved cases of fluindione related acute interstitial nephritis with recovery of renal function after drug withdrawal and prednisone therapy.

Topics: Acute Disease; Acute Kidney Injury; Aged; Anticoagulants; Diuretics; Humans; Kidney Function Tests; Male; Nephritis, Interstitial; Phenindione; Treatment Outcome; Vitamin K

Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Abortion, Spontaneous; Acenocoumarol; Adverse Drug Reaction Reporting Systems; Anticoagulants; Birth Weight; Female; Fetal Diseases; Gestational Age; Humans; Phenindione; Phenprocoumon; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Premature Birth; Prospective Studies; Vitamin K; Warfarin

The purpose of this study was to validate a protocol for dental extraction in patients taking vitamin K antagonists without changing the treatment when the INR is lower than 2.8.. One hundred four extractions (96 patients) were performed during a 9 month period in patients taking vitamin K antagonists. Extraction was performed when the international normalized ratio (INR) was less than 2.8, otherwise, the treatment was modified until the desired INR was reached. Extractions were performed under para-apical and alveolar local anesthesia and sutured with hemostatic gauze.. Three patients developed postoperative bleeding requiring alveolar revision with local application of tranexamic acid and in one case use of a biological glue.. The following protocol can be proposed: ambulatory extraction under local anesthesia with an INR the day before extraction: the extraction is performed if the INR is<=2.8 using hemostatic gauze suture and tranexamic acid in case of persistent bleeding.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Loss, Surgical; Child; Clinical Protocols; Dental Care for Chronically Ill; Female; Humans; International Normalized Ratio; Male; Middle Aged; Oral Hemorrhage; Phenindione; Retrospective Studies; Tooth Extraction; Tranexamic Acid; Vitamin K; Warfarin

Oral anticoagulants and pulse high-dose intravenous methylprednisolone are often administered concomitantly, but no data on potential interactions are available.. To assess possible potentiation of oral anticoagulation by high-dose intravenous methylprednisolone.. Prospective cohort study.. University hospital in Paris, France.. 10 consecutive patients concomitantly receiving methylprednisolone and oral anticoagulants (fluindione and acenocoumarol) and 5 consecutive controls receiving methylprednisolone alone.. Serial determinations of the international normalized ratio (INR) and clotting factors during administration of pulse methylprednisolone. The total plasma fluindione concentration was determined in 3 patients.. The mean INR was 2.75 (range, 2.02 to 3.81) at baseline and increased to 8.04 (range, 5.32 to 20.0) after methylprednisolone administration. Plasma fluindione concentrations and the INR increased after methylprednisolone administration. Methylprednisolone alone did not increase prothrombin time.. The action of oral anticoagulants is potentiated by intravenous high-dose methylprednisolone. The INR should be monitored daily during concomitant administration of these medications.

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Blood Coagulation Factors; Drug Synergism; Female; Humans; Infusions, Intravenous; International Normalized Ratio; Male; Methylprednisolone; Middle Aged; Phenindione; Prospective Studies; Protein C; Protein S; Prothrombin Time; Vitamin K

Topics: 4-Hydroxycoumarins; Aged; Anticoagulants; Dose-Response Relationship, Drug; Hemorrhage; Humans; Indenes; Nadroparin; Phenindione; Recurrence; Risk Factors; Thrombophlebitis; Vitamin K