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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., (© 2018 by The American Society of Hematology.)

Rationale: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy., Patient Concerns: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione., Diagnoses: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome., Intervetions: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started., Outcomes: Clinical improvement ensued. At follow-up the patient is well., Lessons: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

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., Summary: 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., (© 2017 International Society on Thrombosis and Haemostasis.)

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.

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.

Objectives: 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., Methods: We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight., Results: 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., Conclusions: 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.

Enzymatic creatinine assays are considered superior to Jaffe assays due to greater analytical specificity. We report a case of phenindione interference with an enzymatic assay resulting in significant misclassification in a patient with chronic kidney disease (CKD). Analysis of creatinine values of a further 36 patients who were treated with phenindione showed significant negative interference of phenindione with the Roche enzymatic creatinine assay.

Introduction: Switching from fluindione, an indanedione vitamin K antagonist derivative, to warfarin, a coumarin one, or vice versa, requires to know the relationships between dosages of these two molecules., Methods: We conducted a prospective study in 288 consecutive patients aged 70 years and over, converted from fluindione to warfarin. Patients who were retained for the analysis were those for whom maintenance dosages were obtained for both vitamin K antagonists., Results: Eighty-two patients, mean aged 83 ± 6 years, were analysed. The average daily maintenance dosages were 13.8 ± 6.7 mg (range 5-35) and 3.7 ± 1.7 mg (range 1-8) for fluindione and warfarin, respectively. Using a linear regression model, we built a transition algorithm for the maintenance dosages of warfarin and fluindione., Conclusion: This is the first study to propose a conversion algorithm to help prescribers to estimate the maintenance dosage when it is necessary for a patient to switch from fluindione to warfarin or conversely., (Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Introduction: Regular monitoring of the international normalized ratio (INR) is crucial for dose adjustment of vitamin K antagonists (VKA) to maximize time in therapeutic range (TTR). We compared the use of a mobile electronic assistant INRPlus which proposes patient-specific fluindione doses, to standard fluindione management in a cluster randomized controlled study., Patients and Methods: Twenty clusters of six general practitioners were randomized to adjust fluindione doses in VKA-treated patients either using INRPlus or according to routine practice. TTR was measured over 6 months, along with time spent above or below the recommended INR range, frequency of measurements and related complications., Results: Of the 595 included patients, 551 were assessable (259 INRPlus, 292 control) and had a mean of 1.6 INR measurements/month. TTR was not significantly different between the two groups, 72.7% [Q1: 58.1%; Q3: 90%] in INRPlus patients and 71.2% [Q1: 54.8%; Q3: 88.2%] in control patients (p=0.445). At least 60% time within reference ranges was reported in 73.4% of INRPlus patients and 67.1% of control patients (relative risk 1.09, 95%CI 0.98-1.22, p=0.115). No significant differences were reported between the two groups for time outside reference ranges, frequency of measurements or complications. Eighty-two percent (82%) of patients complying with INRPlus-proposed doses spent more than 60% of TTR versus 66.9% of non-compliant patients and 67.1% of reference patients., Conclusions: In this trial, the use of the INRPlus electronic assistant resulted in a non-significant improvement in TTR that may be due to a higher than expected TTR in the control group., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To establish the prevalence of anticoagulation (vitamin K antagonists) and antiplatelet agent therapy in patients undergoing vitreoretinal surgery and to compare the outcome of peribulbar anesthesia and vitreoretinal surgery between users and nonusers., Methods: We conducted a retrospective case series study in one academic center. No changes in the treatment regimen were made before surgery. Patients were divided into 3 groups: G1, patients with no anticoagulant or antiplatelet therapy; G2, patients treated with anticoagulants; and G3, patients treated with aspirin, clopidogrel, or both., Results: Two hundred and six eyes (206 patients) were included. G1, 144 eyes (69.9%) without any anticoagulant or antiplatelet therapy (69.9%); G2, 12 eyes (5.8%) with anticoagulants; and G3, 44 eyes (21.4%) with antiplatelet agents. Six patients (6 eyes) (2.9%) received both anticoagulant and antiplatelet agents. The incidence of overall and mild postoperative hemorrhagic complications was similar between groups, P = 0.075 and P = 0.127, respectively. However, potential sight-threatening hemorrhagic complications were more frequent in patients receiving antiplatelet agents, P < 0.003., Conclusion: Peribulbar anesthesia for vitreoretinal surgery can probably be performed safely in patients receiving anticoagulants. However, retinal surgeons should be aware that severe bleeding complications are more frequent in patients receiving antiplatelet therapy.

Purpose: 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., Methods: We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000., Results: 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., Conclusions: 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.

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Vitamin K antagonist tablets are often split to fractionate the dose by elderly patients. We performed a study in order to assess the divisibility of one dosage strength of score-lined warfarin and of score-lined fluindione., Methods: Due to a recent change in the pharmaceutical form of fluindione in order to improve the divisibility, the study was performed over 2 different periods (with the « old » and with the « new » pharmaceutical form). In each period, 10 patients mean aged 82 years, 10 relatives, 10 nurses, 10 medical doctors) were asked to split in half warfarin tablets (W2 1(st) period et W2 2(d) period) and fluindione tablets (F2 et F'2), and to split fluindione tablets into 4 fragments (F4 et F'4). The first end-point was the accuracy of splitting estimated by the difference between the real and the expected weight of fragmented tablets. The statistical analysis was performed using an ANOVA test with 2 variables, subject and drug. The difference between the 2 periods were analyzed using an ANOVA test with 2 variables, subject and period., Results: Over the 2 periods, the differences between real and expected weight were of 4.65% for W2 1(st) phase, 9.48% for F2, 15.35% for F4, 5.56% for W2 2(d )period, 4.30% for F'2, and 6.98% for F'4. The quality of splitting was statistically poorer in the elderly patient group compared to other subjects., Conclusion: This study was not design to assess the clinical relevance (bleeding or thromboembolism) or the anticoagulation control of the variations in drug mass due to inappropriate splitting of tablets. However, split form of drugs should be prescribe with caution to elderly patients.

Background: Isolated and spontaneous dissection of mesenteric arteries is a rare entity; a little more than 50 cases have been reported in medical literature. There is no therapeutic consensus concerning this type of lesion., Methods: In this study, we report the results of our treatment based on a conservative approach. This retrospective study concerns eight patients with dissection of the celiac trunk and/or of the upper mesenteric artery (UMA) who were treated between 2002 and 2006. Because these patients were not presenting with acute intestinal ischemia diagnosed by clinical examination or paraclinical tests (medical imaging/biology) or with vital complications, they were treated with an efficient anticoagulation (heparin followed by anti-vitamin K) for 3 to 6 months. Endovascular or surgical treatment was used as the first option in patients with obvious intestinal ischemia or likely to have an arterial rupture, and also when medical treatment had failed. Clinical and radiological follow-up was at 1 month, 3 months, 6 months, and 1 year and then every year. Seven men and one woman (mean age, 48.2; age range, 38-53 years) were treated. Six patients presented with isolated dissection (celiac trunk=4, UMA=2). One patient had a celiac trunk and a UMA dissection and one had a celiac trunk and a UMA dissection along with a dissection of his two renal arteries. On entering the hospital, a patient was operated on for mesenteric ischemia related to a stenosis of the upper mesenteric artery (upper aortomesenteric bypass); a covered stent was implanted in the celiac trunk of another patient presenting with a contained rupture., Results: Both patients were successfully treated. Six patients were medically treated. One of them required an aortohepatic bypass to treat an aneurysmal evolution of the celiac trunk revealed by a computed tomography scan obtained 1 month after the symptoms had begun. In one patient, the dissection remained stable on imaging. Four patients were cured, with a mean 20.1-month follow-up., Conclusion: Conservative treatment of spontaneous dissections of mesenteric arteries is possible when there are no complications, and it gives satisfactory results provided regular clinical and radiological checking is performed.

Amebiasis remains a major public health issue in most of the world. Amebic liver abscess is the most common extraintestinal manifestation. A complication such as venous obstruction associated with amebiais is rare. We report a thrombosis in hepatic veins associated with amebic hepatic abscess in a traveler.

No data are available on the efficacy and safety of a combination of fondaparinux and thrombolysis in the setting of high to intermediate risk pulmonary embolism (PE). Patients submitted to thrombolysis and fondaparinux, presenting with > or =1 of the following criteria were included: (1) cardiogenic shock, (2) syncope, (3) > or =1 proximal thrombo-embolus at CT scan, (4) positive troponin test, (5) echocardiographic findings indicating right ventricular (RV) dysfunction. In-hospital results included death, recurrent PE, persistent RV dysfunction at 48 h echocardiography, bleeding complications. Twenty seven patients were included; 22 received a 2 h infusion of rt-PA and 5 received a 2 h infusion of streptokinase. Ten patients presented with cardiogenic shock (37%), 8 with syncope (30%), all had RV dysfunction. 82% of patients had an uneventful in-hospital course. One patient died during hospital stay from refractory shock. Thrombolysis failed in 2 patients (7%), requiring successful rescue surgical embolectomy. Bleeding events occurred in 2 patients (7%), of whom 1 required blood transfusion. Despite the small sample size, our data suggest that fondaparinux procures adequate tolerability compared to standard current therapy in combination with thrombolysis in high to intermediate risk PE.

Introduction: Among microangiopathic disorders of pregnancy, catastrophic antiphospholipid syndrome (CAPS) is a maternal and fetal life-threatening disorder. Hepatic involvement of this multi-systemic disorder can be confused with HELLP syndrome, occurring usually later in the course of pregnancy., Case Report: We report a case of probable CAPS with hepatic disease in a pregnant woman at 13 week's gestation, with antiphospholipid syndrome and biological features of HELLP syndrome. Unspecific hepatic imaging, well-described in our case allowed undelayed therapy., Conclusion: CAPS and HELLP syndrome, both severe microangiopathic disorders, may be associated. Nosological distinction does not modify treatment strategy, which is a maternal and foetal emergency, but their overlapping requires aggressive and early management.

We report a 24-year-old man with a known Behcet's disease who was lost to follow-up for a year. The patient was admitted for the association of scrotal ulceration and inguinal folliculitis, suggesting a Behcet's disease flare-up. Necrotizing course of the folliculitis led to the diagnosis of skin infection caused by a community-acquired methicillin-resistant Staphylococcus aureus strain, carrying Panton-Valentine leukocidin genes. Bacteriological analysis should be mandatory in the absence of specific criteria for the diagnosis of Behcet's disease.

(1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhoea, the earliest sign in patients with renal failure and in the elderly.

Authors report a case of a 77 years old man who developed a small bowel mesenteric hematoma as consequence of an unusual complication from a long term oral anticoagulation treatment. Computed tomoangiography helpfully suggests diagnosis of a mesenteric hematoma and refuts an organic cause as vascular anomalies, by an equivalent method to conventional angiography, noninvasely. In our case report, patient's deterioration justified an emergency surgery corroborating medical imager findings. Authors review the rare cases previously reported.

Introduction: Fluindione (Previscan) is an oral anticoagulant belonging to the vitamin K antagonist class and is very widely used in France. While bleeding is a common complication, severe immunoallergic reactions are less frequent. The authors report a case of drug-induced hypersensitivity syndrome., Case Report: A 75 year-old woman was hospitalized for diffuse erythematous papular rash associated with facial oedema. These symptoms appeared 3 weeks after the beginning of treatment with fluindione, allopurinol and perindopril. Laboratory tests showed hyperleukocytosis, mixed hepatitis and moderate renal failure, with the entire picture being evocative of drug-induced hypersensitivity reaction. The eruption was associated with eosinophilia, hepatic cytolysis with cholestasis, and acute renale failure. While allopurinol and perindopril were stopped definitively, fluindione was only suspended temporarily following overdosage. On reintroduction, rapid recurrence of clinical and biologic signs was observed with increased severity. The skin rash resolved completely on withdrawal of the drug. Patch tests performed later were positive for fluindione and negative for allopurinol and perindopril., Discussion: These manifestations were consistent with the diagnosis of drug-induced hypersensitivity syndrome due to fluindione. Very few cases have been described with fluindione despite widespread prescription of the treatment is in France. While there may be no skin involvement, immunoallergic signs such as fever, hepatitis and acute tubular interstitial nephritis have been described with fluindione and these may be related to this syndrome (DRESS - Drug Reaction with Eosinophilia and Systemic Symptoms). Skin patch testing, which is easily performed, can be extremely helpful in determining a causal relationship with medication.

Background: The quality control of oral anticoagulant therapy (OAT) during the initiation and maintenance treatment is generally poor. Physicians' ordering of OAT (especially fluindione and warfarin) can be improved by dose adjustment algorithms, taking into account the results of International Normalized Ratio (INR). Reminders at the point of care, computerized or not, have been demonstrated to be effective in changing physicians prescription behavior.However, few studies have addressed the benefit of personalized reminders versus non personalized reminders, whereas the personalized reminders require more development to access patient record data and integrate with the computerized physician order entry system. The Hospital Information System of George Pompidou European Hospital integrates an electronic medical record, lab test and drugs order entry system. This system allows to evaluate such reminders and to consider their implementation for routine use as well as the continuous evaluation of their impact on medical practice quality indicators. The objective of this study is to evaluate the impact of two types of reminders on overtreatment by oral anticoagulant: a simple reminder of text formatted dose adjustment table and a personalized recommendation for oral anticoagulant dose and next date of INR control, adapted to patient data. Both types of reminders appear to the physician at the moment of drug ordering.

Rare cases of coagulaopathies from dermal absorption of hydroxycoumarin derivatives have been reported. We report the first case of dermal absorption of an indandione derivative rodenticide causing severe coagulopathy. An 18-y-o male worker at a pest exterminating company spilled a concentrated liquid preparation of 0.106% diphacinone in his boot. He did not remove the boot or wash the area for 6 to 8 h. Seven days later he presented to the emergency department with flank pain, hematuria and epistaxis. Laboratory values were PT > 40 sec, PTT > 90, Hb 16.2, and platelets 273. Urinalysis reported gross hematuria with RBCs too numerous to count. Prolonged bleeding was noted at i.v. puncture sites. Initial therapy included i.m. injection of vitamin K and nasal packing. The patient's religious beliefs precluded the use of blood products. The patient was admitted for observation until PT was controlled. He was discharged on high dose vitamin K p.o. dose titrated to the international normalized ratio measured every 48 h. After 2 w, a dose of 100 mg vitamin K/d was set and the patient was followed as an outpatient for 3 mo. Vitamin K therapy was tapered and discontinued 60 d post-exposure with no further elevation in PT. Diphacinone was detected in a serum sample drawn 60 d post-exposure using gradient and isocratic HPLC methods with fluorescence and UV detection. Factors increasing the dermal absorption of the diphacinone were: prolonged skin contact in a confined area and exposure to a concentrated solution.

Objective: To evaluate the therapeutic impact of an education program on patients undergoing oral anticoagulation treatment, within the hospital of Annecy (France)., Material and Methods: 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., Results: 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)., Conclusion: 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.

There is limited information regarding the interaction of hormone replacement therapy (HRT) and oral anticoagulants. Following the acute over-anticoagulation of two women shortly after the initiation of tibolone, we have undertaken a retrospective review of anticoagulated women to determine if the dose of oral anticoagulants and quality of anticoagulant control are affected by the introduction of HRT. We demonstrate that acute over-anticoagulation consistently occurs following the commencement of tibolone and requires anticoagulant dose modification to re-establish target international normalised ratio (INR). In contrast, non-tibolone HRT preparations do not consistently alter anticoagulant control or dose requirements.

Introduction: There is no validated method to predict the daily maintenance dosage of oral anticoagulation treatment by fluindione in the elderly patients. The aim of our prospective study was to look for a relation between INR at day 2 after a fixed dosage of fluindione and the daily maintenance dosage of fluindione necessary to obtain an INR value between 2 and 3., Patients and Methods: Ten milligrams of fluindione were administered on first and second day of treatment. INR was determined the third day., Results: From this value, we were able to determine the daily dosage of fluindione (+/- 5mg) that maintained a steady state INR value between 2 and 3., Conclusion: In these very elderly patients, there was a relation between INR at the third day after a fixed dosage of fluindione and the daily maintenance dosage of fluindione necessary to obtain an INR value between 2 and 3.

Patients and Methods: Between 1997 and 2001, 150 children (one month to 16 years of age) were treated with oral anticoagulants after cardiac surgery (Fontan's operations and congenital heart diseases without valvulopathy: 62%, valvular prosthesis: 20%, arrhythmia: 4.6%, thrombosis: 4%, other: 9.4%). They were first treated by either unfractionated heparin (49%) or nadroparin (51%), then by acenocoumarol (n1 = 114) or fluindione (n2 = 36) until steady state., Results: The retrospective analysis of data (age, body weight, international normalized ratio, loading and maintenance doses, time to achieve the steady state) led to the building of a dosage nomogram usable in pediatrics., Conclusion: We demonstrated that the mean maintenance dose depended on age and weight. After three years, that dose (mg/kg) was getting close to adult values; it was higher before three years of age, especially before 12 months (p < 0.01), and very variable from a child to another. The recommended loading dose should be as close as possible to the effective maintenance dose: within that cohort, about 0.14 and 0.05 (acenocoumarol) or 1.1 and 0.40 mg kg-1 day-1 (fluindione), before 12 months and after three years respectively.

The effect was determined of a single dose of 2 mg kg-1 diphacinone on three blood-clotting parameters [Prothrombin Time (PT), Partial Thromboplastin Time (PTT), and Protein Induced by Vitamin K Absence or Antagonists (PIVKA)] over a 120-h period in California ground squirrels, Spermophilus beecheyi. Diphacinone resulted in elevated PT, PTT and PIVKA within 24 h of squirrels receiving the dose. The most significant change was observed 72 h after dosing. As time following diphacinone dosing increased, there was higher individual variation in blood-clotting time. We suggest that increasing the interval between field bait applications should still result in squirrel mortality but reduce the potential for secondary hazards that may occur when squirrels have the opportunity to consume more than one lethal dose of diphacinone.

Clinical evaluation of thromboplastins manufactured by RENAM (Moscow) with international index of sensitivity (IIS) 1.1-1.5 and comparison of the results with the data obtained in the same patients with foreign thromboplastins (Dade, USA; Behring, Germany; Diamed, Switzerland) and Mediolab thromboplastins (Russia) manufactured from different raw materials (rabbit brain and human placenta) showed that by sensitivity to indirect anticoagulants, Russian thromboplastins made by RENAM and Mediolab firms are not inferior to the best foreign analogs.

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.

Reports on phenindione toxicity have limited its use as an oral anticoagulant. Our aim was to evaluate its risks in pregnant women. Thirty-one pregnancies in 29 women with mitral (+/-aortic) St. Jude mechanical valves were followed-up prospectively. Eighteen patients received phenindione. Eleven patients (37.9%) received in addition to phenindione 225 mg dipyridamole, which was given in three doses. The target INR was 2.5-3.5 in the former and 2-2.5 in the latter treatment. A fortnight before delivery, intravenous heparinotherapy was substituted. There were no maternal complications, apart from a single postpartum hemorrhage (3.2%). After the deliveries the results were: 26 mature babies (83.9%), 3 premature babies (9.7%) and 2 cases of stillbirth (6.4%). Outcome was dose related; being 57.2+/-20.9 mg/day for mature babies and 82.5+/-11.2 mg/day for prematures and stillbirths (P=0.016). Phenindione provided safe and effective anticoagulation during pregnancy. A larger study is necessary to confirm the relationship between the dosage and outcome.

Background: A combination of low-dose aspirin with anticoagulants may provide better protection against thromboembolic events compared to anticoagulants alone in high-risk patients with atrial fibrillation., Objective: Evaluation of the preventive efficacy against nonfatal thromboembolic events and vascular deaths of the combination of the oral anticoagulant fluindione and aspirin (100 mg) in patients with high-risk atrial fibrillation., Methods: A multicenter, placebo-controlled, double-blind, randomized trial was conducted at 49 investigating centers in France. Atrial fibrillation patients with a previous thromboembolic event or older than 65 years and with either a history of hypertension, a recent episode of heart failure or decreased left ventricular function were included in the study. Patients were treated with fluindione plus placebo (i.e. anticoagulant alone) or fluindione plus aspirin (i.e. combination therapy), with an international normalized ratio target of between 2 and 2.6. The combined primary endpoint was stroke (ischemic or hemorrhagic), myocardial infarction, systemic arterial emboli or vascular death. The secondary endpoint was the incidence of hemorrhagic complications., Results: The 157 participants (average age 74 years; 52% women; 42% with paroxysmal atrial fibrillation) were followed for an average of 0.84 years. Three nonfatal thromboembolic events were observed (1 in the anticoagulation group, 2 in the combination group) and 6 patients died (3 in the anticoagulation group, 3 in the combination group), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe hemorrhagic complications (1 in the anticoagulation group, 2 in the combination group). Nonfatal hemorrhagic complications occurred more often in the combination group (n = 10, 13.1%) compared to the anticoagulation group (n = 1, 1.2%) (p = 0.003)., Conclusion: The combination of aspirin with anticoagulant is associated with increased bleeding in elderly atrial fibrillation patients. The effect on thromboembolism and the overall balance of benefit to risk could not be accurately assessed in this study due to the limited number of ischemic events., (Copyright 2001 S. Karger AG, Basel)

In a previous study, the authors proposed a method to individualize fluindione dosage regimen, based on a pharmacokinetic/pharmacodynamic model describing the evolution of the International Normalized Ratio (INR). In this method, daily maintenance dosage for a target INR depends on the product of individual Cl and C50. The present work shows the results of a follow-up study in 50 patients for whom target INR was 2.5. INR measurements and dosage regimens were recorded both during hospital stay and during the 1st month of treatment. Patients were defined as equilibrated after 1 month if the last two INRs were in the range 1.5-3.5 under a stable dosage regimen. Actual maintenance dose was compared with the dose predicted using the three first INRs measured in the hospital. Intraindividual variability of Cl*C50 between hospital stay and after 1 month was evaluated. After 1 month, only 27 patients (54%) were equilibrated. Actual maintenance dose varied from 5 to 30 mg daily. There was no bias between predicted and actual maintenance dose (1.4 mg), but a large root mean squared error (8 mg) was found. The intraindividual variability in Cl*C50 between hospital and maintenance regimen was high (93%), which may explain the dispersion in the predicted maintenance dose.

Background: Although the addition of 300 mg dipyridamole to oral anticoagulants has been shown to decrease thromboembolic events after cardiac valve replacement, reports of combined therapy were few and some showed significant dipyridamole-related side effects and intolerance. The aim of this study was to compare the clinical effect of a standard monotherapy (targeting an international normalized ratio - INR - between 2.5 and 3.5) to a less intensive regimen (targeting an INR between 2 and 2.5) combined to a small dose of dipyridamole (225 mg/day)., Methods: Between January 1990 and December 1998, 486 young rheumatic patients with a St Jude mitral valve prosthesis were assigned to follow either standard monotherapy (294 patients) or low-level combined therapy (192 patients). Phenindione has been the anticoagulant of choice. Up to a maximum daily dose of 100mg, patients failing to achieve their target INR range were shifted to warfarin therapy. Prothrombin time was checked monthly and asymptomatic patients with a too low or a too high INR (<1.3 or >5) were briefly hospitalized for INR control. Complete blood picture, renal and hepatic profiles and full echocardiographic study were done biannually., Results: With the exception of a significantly larger left atrium in patients on low-level combined therapy (P=0.001), both groups were comparable as regards to age and sex distribution, number of patients with atrial fibrillation, left atrial thrombus and history of stroke. Patients were monitored for 1712.6 pt yr and follow-up was 96.7% complete. No phenindione-related complications were observed (mean dose 62.3+/-21.4 mg), 20 patients (4.1%) had failed to achieve their target INR range and were switched to warfarin and only three patients (1.6%) had tolerable dipyridamole-related side effects. Compared to standard monotherapy, patients on low-level combined therapy showed significantly lower annualized rates: thromboembolism (1.6 vs 0.43%: risk reduction 71%; P=0.05), thromboembolism and hemorrhage (2.7 vs 0.7%: risk reduction 72%; P=0.005), death due to valve thrombosis or stroke (1.17 vs 0. 14%: risk reduction 81%; P=0.04) as well as both non-fatal (3.3 vs 1. 57%: risk reduction 51%; P=0.04) and total late postoperative complications (5.35 vs 3.14%: risk reduction 40%; P=0.04); respectively. However, total late mortality (32 patients; 1.8% per pt yr) was comparable among both groups., Conclusion: Low-level anticoagulation with phenindione combined to low dosage of dipyridamole was clinically more effective than the higher standard monotherapy. With respect to the prescribed doses, both drugs were well tolerated by almost all patients. Use of dipyridamole did not influence overall patients' survival.

Beraprost sodium (BPS), an orally active PGI2 (prostaglandine 12) analogue possesses vasodilatating and platelet aggregation inhibiting properties. It is being developed in peripheral arterial occlusive disease. As in future clinical practice BPS might be co-prescribed with oral anticoagulants, we investigated its interaction with fluindione, a vitamin K antagonist in healthy subjects in a randomised, double-blind, placebo-controlled, crossover study. Twelve healthy Caucasian male subjects randomly received BPS 40 microg t.i.d. or placebo for 3 days. There was a 7 day wash out between the two treatment periods. On day 3 of each treatment, the subjects ingested concomitantly a single oral dose of 20 mg of fluindione. The main assessment criterion was fluindione's pharmacokinetics. Secondarily, pharmacodynamic measurements of coagulation (prothrombin time, and International Normalised Ratio, INR) and platelet function (in vitro closure time assessed by PFA-100) were performed. Fluindione was assayed by HPLC with UV detection up to 96 h post-drug. No statistical difference could be evidenced on any fluindione pharmacokinetic parameters between BPS and placebo phases: t 1/2 (h): 35.9 (8.2) vs. 34.0 (4.2) [90% CI 105.8 (95.5-116.2)]; T(max) (h): 2.0 (0.5-6.0) vs. 4.0 (0.5-6.0) [90% CI 136.4 (70.7-208.9)]; Cmax (mg/L): 3.1 (0.6) vs. 2.9 (0.5) [90% CI 94.1 (85.8-103.2)]; AUC 0-inf (mg/h/L): 117.0 (31.5) vs. 113.9 (33.8) [90% CI 97.6 (87.5-108.8)]. The studied doses of BPS did not affect platelet function, at least as assessed by the in vitro platelet function testing. Twenty milligrams of fluindione marginally modified the PT ratio and INR, however, no statistically significant difference was found between BPS and placebo phases. In conclusion, a 3 day regimen of BPS 40 microg t.i.d. by oral route does not seem to affect pharmacokinetic parameters of a fluindione 20 mg single dose.

Background: Oral anticoagulants and pulse high-dose intravenous methylprednisolone are often administered concomitantly, but no data on potential interactions are available., Objective: To assess possible potentiation of oral anticoagulation by high-dose intravenous methylprednisolone., Design: Prospective cohort study., Setting: University hospital in Paris, France., Patients: 10 consecutive patients concomitantly receiving methylprednisolone and oral anticoagulants (fluindione and acenocoumarol) and 5 consecutive controls receiving methylprednisolone alone., Measurements: 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., Results: 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., Conclusions: The action of oral anticoagulants is potentiated by intravenous high-dose methylprednisolone. The INR should be monitored daily during concomitant administration of these medications.

We report three cases of severe haemorrhagic rupture of luteal ovarian cyst requiring surgical haemostasis in young women treated with long-term oral anticoagulation for antiphospholipid syndrome (APS) who used no contraception. At the time of bleeding, the international normalized ratios were 3.78, 4.24, and 7.11. Anticoagulation was resumed post-operatively, in association with antigonadotropic progestins to induce ovulatory suppression. A systematic use of these progestins should probably be discussed in young women receiving long-term warfarin for APS. Ovarian haemorrhage must be considered when such patients develop acute abdominal pain.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Objective: To compare oral anticoagulant treatment (fluindione) started on either the 1st or the 10th day of a low-molecular-weight heparin (enoxaparin) treatment for deep vein thrombosis confirmed by venography., Design: An open, multicenter, randomized study in two parallel treatment groups., Interventions: All patients received enoxaparin, 1 mg/kg s.c. twice daily, and oral fluindione, 20 mg once daily, either beginning on day 1 or on day 10 of the enoxaparin treatment. Enoxaparin was discontinued once the international normalized ratio under fluindione was stable between 2.0 and 3.0 over 2 days. Fluindione treatment was maintained during a 3-month follow-up period., Outcome Measurements: Specific examinations (venography and/or V/Q lung scanning and/or angiography) were performed only in the event of a clinically suspected recurrence of venous thromboembolism during the 3-month follow-up period. All cases were blindly assessed by an independent Reading Committee., Results: A clinically suspected venous thromboembolism was confirmed by objective tests in 1 of 223 patients (group of delayed introduction of fluindione; n = 111). Equivalence was demonstrated between the two treatment schedules (p < 0.0001) for a maximal difference of 10% (90% confidence interval: -2.42 to 0.58). The mean duration of hospitalization was significantly reduced (p = 0.0001) in the group with early introduction of fluindione. The incidence of hemorrhage was comparable between the two treatment groups., Conclusion: Early and delayed introduction of oral anticoagulant treatment in association with subcutaneous enoxaparin in patients with deep vein thrombosis was shown to be equivalent in preventing the recurrence of venous thromboembolism. In patients with early introduction of oral anticoagulant, hospitalization was significantly reduced.

Due to large inter-individual variations, the dose of vitamin K antagonist required to target the desired hypocoagulability is hardly predictible for a given patient, and the time needed to reach therapeutic equilibrium may be excessively long. This work reports on a simple method for predicting the daily maintenance dose of fluindione after the third intake. In a first step, 37 patients were delivered 20 mg of fluindione once a day, at 6 p.m. for 3 consecutive days. On the morning of the 4th day an INR was performed. During the following days the dose was adjusted to target an INR between 2 and 3. There was a good correlation (r = 0.83, p < 0.001) between the INR performed on the morning of day 4 and the daily maintenance dose determined later by successive approximations. This allowed us to write a decisional algorithm to predict the effective maintenance dose of fluindione from the INR performed on day 4. The usefulness and the safety of this approach was tested in a second prospective study on 46 patients receiving fluindione according to the same initial scheme. The predicted dose was compared to the effective dose soon after having reached the equilibrium, then 30 and 90 days after. To within 5 mg (one quarter of a tablet), the predicted dose was the effective dose in 98%, 86% and 81% of the patients at the 3 times respectively. The mean time needed to reach the therapeutic equilibrium was reduced from 13 days in the first study to 6 days in the second study. No hemorrhagic complication occurred. Thus the strategy formerly developed to predict the daily maintenance dose of warfarin from the prothrombin time ratio or the thrombotest performed 3 days after starting the treatment may also be applied to fluindione and the INR measurement.

Follow-up of 7 patients with nephritically active mesangiocapillary chronic glomerulonephritis which received for 22 months combined therapy with prednisone (60 mg), chlorambucil (0.2 mg/kg), curantyl (400 mg), heparin or fenilin has found a significant lowering of proteinuria, hypercreatinemia, a rise in osmotic concentration. A complete remission was achieved in 2 patients, partial in 3 patients, a progression occurred after 8 years in one.