Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study.

BACKGROUND: Poor anticoagulant stability in patients using vitamin K antagonists is a risk factor for both bleeding and thrombosis. In previous studies supplementation with low dose vitamin K(1) was shown to improve the stability of anticoagulant control. We set up a study to confirm earlier reports and to determine the optimal daily dose of vitamin K(1) in preparation of a large study with clinical endpoints. DESIGN AND METHODS: Four hundred patients from two anticoagulation clinics starting with vitamin K antagonists, independently of a possible history of instable anticoagulation, were randomized to receive either placebo or 100, 150 or 200 µg of vitamin K(1) together with their treatment with vitamin K antagonists. The treatment was administered for 6 to 12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups. RESULTS: After adjustment for age, sex, vitamin K antagonist used, anticoagulation clinic and interacting drugs as confounding factors the difference in percentage of time with the International Normalized Ratio within the therapeutic range between the placebo group and the vitamin K(1) groups was 2.1% (95% CI: -3.2% - 7.4%) for the group taking 100 µg, 2.7% (95% CI: -2.3% -7.6%) for the group taking 150 µg and 0.9% (95% CI: -4.5% - 6.3%) for the group taking 200 µg vitamin K(1) group, in favor of the vitamin K(1) groups. The patients from both the 100 µg group and the 150 µg group had a 2-fold higher chance of reaching at least 85% of time with the International Normalized Ratio within the therapeutic range. There were no differences in thromboembolic or hemorrhagic complications between the groups. CONCLUSIONS: In patients starting vitamin K antagonists, supplementation with low dose vitamin K(1) resulted in an improvement of time that anticoagulation was within the therapeutic range. Differences between doses were, however, small and the improvement is unlikely to be of clinical relevance. For future studies we recommend selecting only patients with instable anticoagulant control. (This study was registered at www.isrctn.org as ISRCTN37109430).

Could geriatric characteristics explain the under-prescription of anticoagulation therapy for older patients admitted with atrial fibrillation? A retrospective observational study.

BACKGROUND: Anticoagulation therapy with anti-vitamin K (AVK; vitamin K antagonist) for the prevention of thromboembolism in patients with atrial fibrillation (AF) is based on information derived from numerous well constructed, randomized controlled trials. Despite this conclusive evidence of efficacy, several studies have shown that 'real world' use of AVK in patients with AF is suboptimal. Our hypothesis was that geriatric characteristics (functional impairment, cognitive disorders, malnutrition, risk for falls, depression) could be an explanation for the underprescription of AVK in older patients with AF. OBJECTIVE: To analyse the barriers to the prescription of AVK therapy, with special attention on geriatric characteristics. METHODS: This was a retrospective study of 768 consecutive geriatric patients admitted to an acute geriatric unit of an academic hospital between April 2006 and November 2008. Data from comprehensive geriatric assessments were collected from computerized medical charts. RESULTS: Analysis of data from the 768 medical charts showed that 111 patients (14%) presented with AF. Among the 111 patients (72% women), 45% were living in an institution before admission. These patients presented a high prevalence of geriatric syndromes: cognitive disorders 59%, malnutrition risk 59%, incontinence 35%, depression 37%, and falls 61%. Ninety percent of the patients had an Identification of Seniors At Risk (ISAR) questionnaire score ≥2, which indicates an increased risk of frailty and functional decline during hospitalization. The prevalence of conditions measured by the CHADS(2) (congestive heart failure, hypertension, age >75 years, diabetes mellitus and previous stroke or transient ischaemic attack [TIA]) clinical prediction scale was as follows: heart failure 19%, hypertension 79%, age >75 years 95%, diabetes 15% and stroke 24%. The mean ± SD number of daily classes of drugs received at admission was 7.1 ± 3.3 (median 7, range 0-20). Forty-nine percent of patients had not received any AVK treatment before admission. The level of functional dependence for basic and instrumental activities of daily living did not differ between patients receiving AVK before admission and those not receiving AVK. Similarly, the proportion of geriatric problems (cognitive, malnutrition, depression and falls) did not differ between these two groups. To determine whether the decision to administer AVK therapy before admission was influenced by the risk of an embolic stroke, determined by the presence of CHADS(2) conditions, we compared the proportions of patients who fulfilled those conditions in each group: again, no difference was found. CONCLUSIONS: Almost half of the patients presenting with AF did not receive any AVK therapy before admission. In this population, in which most patients had multiple impairments, no single impairment or geriatric characteristic was identified as a barrier to AVK use. It is possible that combinations of impairments and geriatric characteristics were barriers to the prescription of AVK therapy across the whole of this population. More research is needed to identify and clarify the relative importance of patient-, physician- and healthcare system-related barriers to the prescription of AVK therapy in older patients with AF.

[Advances in the prevention of cerebral ischaemia due to atrial fibrillation]. / Avances en la prevención de la isquemia cerebral por fibrilación auricular.

INTRODUCTION: Stroke and atrial fibrillation (AF) are a real vascular epidemic, and the consequences are disastrous. The most common complication of AF is stroke. BACKGROUND: The correct aetiological diagnosis of stroke is essential for adequate prevention. The percentage of cryptogenic ischaemic strokes is far too high and the detection of AF needs to be improved. Cardio-embolic cerebral ischaemia due to AF is preventable, however due to medical inertia, the lack of compliance by the patient, and the problems with oral vitamin K antagonist anticoagulants, means that many patients with AF are at risk of suffering from a stroke. CONCLUSIONS: The significant recent advances with drugs such as dronedarone and dabigatran, provide real hope for an improvement in its prevention, and for this reason neurologists must know about them.

Accuracy of a portable international normalized ratio monitor for patients receiving a low molecular weight heparin as a bridge pending full oral anticoagulant efficacy.

BACKGROUND: Point of care (POC) devices measuring the international normalized ratio (INR) are accurate for patients with stable disease, but their efficiency has not been prospectively assessed during the "bridging period" when patients are receiving a low molecular weight heparin (LMWH) on top of a vitamin K antagonist (VKA) until the target INR is reached. METHODS: 188 dual INR measurement using the POC (INR(POC)) and the laboratory (INR(lab)) at the same time were consecutively determined : 69 in patients receiving LMWH+VKA (bridging group) and 119 in patients receiving only a VKA (control group). INRpoc was compared to INR(lab). RESULTS: Test strip failure rate was higher in the bridging group than in the control group (29% vs 4%; p<0,001). In successful tests, POC accuracy was not modified by LMWH administration: the correlation coefficients between POC and lab INR values for the bridging group and the control group were 0,81 and 0,87 respectively, and the relative measure of divergence (RMD=INR(lab) - INR(poc)/INR(lab)) was lower in the bridging group than in the control group (4+/-7% vs 10+/-14%; p=0,02). Finally, clinically relevant agreement between POC and laboratory was of 90% in the bridging group and 92.1% in the control group (p=0.6). CONCLUSION: With the POC used (INRatio), in patients receiving LMWH when the POC gives a result, it is as accurate as in patients not receiving a LMWH.

Differential inhibition of thrombin generation by vitamin K antagonists alone and associated with low-molecular-weight heparin.

Vitamin K antagonists (VKA) treatment starts with co-administration of low-molecular-weight heparin (LMWH). The anticoagulation induced by the two drugs is still not well determined. In the present study we used thrombin generation assay to evaluate the hypo-coagulation induced by treatment with VKA and by the combination of VKA with LMWH. Tissue factor triggered thrombin generation in platelet-poor plasma was assessed in samples from 15 healthy volunteers, 97 samples from patients treated with VKA and 41 samples from patients receiving enoxaparin and VKA. Patients were classified according to international normalised ratio (INR) level (<2, 2-3 and >3). In plasma samples from patients treated with VKA having INR 2-3 the inhibition of thrombin generation reached 50% compared to controls. In samples with INR>3 this inhibition was 80%. In samples from patients receiving both LMWH and VKA, thrombin generation was significantly decreased compared to the controls and VKA group. In samples with an INR 2-3 obtained from patients treated with LMWH and VKA, the inhibition of thrombin generation was similar to that observed in samples with an INR>3 obtained from VKA treated patients. Thrombin generation assay is sensitive to detect the global the anticoagulant effect produced by the association of LMWH and VKA. For equal INR dual anticoagulant treatment induces significantly more profound inhibition of thrombin generation compared to treatment with VKA alone. The clinical relevance of this observation merits to be studied in prospective studies in patients with defined indications of anticoagulant therapy.

Bench-to-bedside review: Optimising emergency reversal of vitamin K antagonists in severe haemorrhage - from theory to practice.

Critical care physicians are increasingly facing patients receiving oral anticoagulation for either cessation of major haemorrhage or to reverse the effects of vitamin K antagonists ahead of emergency surgery. Rapid reversal of anticoagulation is particularly essential in cases of life-threatening bleeding. In these situations, guidelines recommend the concomitant administration of prothrombin complex concentrates (PCCs) and oral or intravenous vitamin K for the fastest normalisation of the international normalised ratio (INR). Despite their universal recommendation, PCCs remain underused by many physicians who prefer to opt for fresh frozen plasma despite its limitations in anticoagulant reversal, including time to reverse INR and high risk of transfusion-related acute lung injury. In contrast, the lower volume required to normalise INR with PCCs and the room temperature storage facilitate faster preparation and administration time, thus increasing the speed at which haemorrhages can be treated. PCCs therefore allow faster, more reliable and complete reversal of vitamin K anticoagulation, especially when administered immediately following confirmation of haemorrhage. In the emergency setting, probabilistic dosing may be considered.

[Initial treatment of venous thromboembolic events]. / Traitement initial de la maladie thrombo-embolique veineuse.

Initial treatment of venous thromboembolic events is currently based on antithrombotics. This treatment is validated and identical for deep vein thrombosis (DVT) and pulmonary embolism. For distal DVT, this treatment has still to be validated. This reference therapeutic strategy is firstly parenteral and based on low-molecular-weight heparins (LMWH) or fondaparinux, subcutaneously prescribed at fixed dosage based on body weight without any systematic dose adjustment on hemostasis tests. Unfractionated heparin is steel the reference treatment in case of severe renal insufficiency. This parenteral treatment has to be relieved by vitamin K antagonists (VKA). VKA has to be co-administrated for at least 3 days, without any loading dose and can be early initiated. VKA dose needs to be adjusted in order to maintain INR between 2 and 3. However, in case of cancer, LMWH have to be carried on for 6 months. A part this antithrombotic treatment, thrombolytics are recommended in case of massive PE and vena cava filter should be used in case of recurrence despite adequate antithrombotic treatment or in case of contraindication to antithrombotic.

Low-molecular-weight heparin in pregnant women with prosthetic heart valves.

BACKGROUND AND AIM OF THE STUDY: Low-molecular-weight heparin (LMWH) is considered a recommended anticoagulation option in pregnant women with prosthetic heart valves. However, few data are available regarding the efficacy and safety of LMWH in this setting. METHODS: In 1999, the authors' institution developed a standardized anticoagulation protocol for pregnant women with prosthetic heart valves, which included LMWH administered between six and 12 weeks' gestation, and after 36 weeks, with prespecified target levels, and additional low-dose aspirin. Herein is presented the initial experience using this anticoagulation regimen. RESULTS: Among five women with prosthetic heart valves treated with LMWH during part of their pregnancy, four had uneventful pregnancies while one suffered a coronary artery embolus. A review is provided of the current state of knowledge regarding anticoagulation in pregnancy, with emphasis placed on the importance of strict monitoring of anticoagulation levels. CONCLUSION: Given the drawbacks of other forms of anticoagulation, and within the constraints of available data, LMWH appears--when administered with caution--to be an acceptable alternative in pregnant women with prosthetic heart valves.

Antithrombotic therapy for stroke prevention in atrial fibrillation.

Atrial fibrillation (AF) is the most potent common risk factor for ischemic stroke. The number of Americans with nonvalvular AF is expected to increase markedly over the next several decades, making AF-related stroke an important public health concern. Given the individual and societal burden associated with AF-related stroke, efforts to identify and implement efficacious and acceptably safe therapeutic stroke prevention strategies are paramount. This article reviews the existing randomized trial evidence supporting the efficacy of oral vitamin K antagonists (ie, warfarin) or aspirin for preventing thromboembolism in AF, as well as completed and ongoing studies exploring novel antithrombotic agents including the oral direct thrombin inhibitor, ximelagatran, other antiplatelet agents (eg, clopidogrel), factor Xa inhibitors, and other pharmacological agents and additional therapeutic approaches such as mechanical devices and surgical procedures to obliterate the left atrial appendage.

[Influence of oral anticoagulant treatment on D-dimers levels]. / Influence des traitements anticoagulants oraux sur la mesure des D-dimères.

The usefulness of D-dimers determination for the exclusion of deep vein thrombosis (DVT) has been extensively studied. The persistence of high levels of D-dimers has also been suggested as a marker of hypercoagulability in rare studies and might be used to identify patients at risk for recurrent DVT. We have studied the influence of oral anticoagulant treatment in 149 patients, 17 to 84 year-old, with a history of venous thromboembolism; 81 received oral anticoagulant treatment, 68 did not. Patients with known reasons for high level of D-dimers such as cancer were excluded. Thrombophilia was found in 84 patients. D-dimers measurements were performed by ELFA technique using Vidas (bioMérieux, France) analyzer. A significantly lower level of D-dimers was observed in patients under oral anticoagulant compared to patients without this treatment, 197 +/- 134 mug/L versus 399 +/- 239 mug/L, respectively (p < 0.001). A level upper the normal value (500 mug/L) was found in only 3 patients out of 81 receiving an oral anticoagulant treatment as compared with 21 of the 68 patients without treatment. This decrease of D-dimers in patients receiving oral anticoagulants was the same in the different age populations. There was no correlation between INR and D-dimers levels in this study. The clinician should be informed of the decrease of D-dimers in patients treated with anticoagulants. The decrease of D-dimers plasma level during oral anticoagulant treatment suggest that D-dimers concentration in plasma is an indirect marker of reduced clotting activity in vivo.

An ibuprofen-antagonized plasmin inhibitor released by human endothelial cells.

Serum-free culture medium harvested from endothelial cell monolayer cultures derived from human scars and dermis was examined for inhibition of fibrinolysis using a fibrin plate assay. Human cultured fibroblasts and smooth muscle cells did not produce any detectable inhibitory activity. The inhibitor is spontaneously released from the cultured endothelial cells over time. In the fibrin plate assay of plasmin-induced fibrinolysis, one nonsteroidal antiinflammatory (NSAI) drug, ibuprofen, was demonstrated to antagonize the inhibition of fibrinolysis. The antagonistic activity of ibuprofen appears unrelated to its NSAI drug activity because other NSAI drugs such as indomethacin and tolmetin have minimal antagonistic activity. Heating the cultured endothelial cells to 42 degrees C stimulates greater release of the inhibitor in a shorter period of time. This plasmin inhibitor, which is produced by endothelial cells, may contribute to postburn vascular occlusion, leading to secondary progressive necrosis in burn-traumatized patients.

Anti-plasmin inhibitor. V. Structures of novel dimeric eckols isolated from the brown alga Ecklonia kurome OKAMURA.

6,6'-Bieckol (1), 2-O-(2,4,6-trihydroxyphenyl)-6,6'-bieckol (4), and 8,8'-bieckol (2), bispolyphenols with a dibenzo-1,4-dioxin skeleton, have been isolated as potent anti-plasmin inhibitors from the brown alga Ecklonia kurome OKAMURA. Their structures have been determined to be dimers of eckol linked at the C-6 or C-8 positions, through an aryl-aryl bond on the basis of spectral data. Their inhibitory actions on anti-plasmins (alpha 2-macroglobulin and alpha 2-plasmin inhibitor) and some proteases have been examined.

Ibuprofen as an antagonist of inhibitors of fibrinolysis in wound fluid.

Fibrin plate assay revealed that rat serum and wound fluid harvested from seven day subcutaneously implanted wound chambers prevented fibrinolysis. Samples of wound fluid from one to four hour burns displayed greater inhibiting activity than unburned or 24 hour old burns. Ibuprofen, a non-steroid anti-inflammatory drug, reversed the blocking of fibrinolysis in wound fluid, but it had no action on rat serum. The activity of ibuprofen appears unrelated to the synthesis of prostanoids. Fractionation of wound fluid and serum by column chromatography showed differences in elutions of inhibitors of fibrinolysis. Serum fractions having molecular weights greater than 60,000 prevented fibrinolysis and they were unaffected by the addition of ibuprofen. Fractionations of wound fluid produced a number of inhibitors, some of which had molecular weights of approximately 40,000. This inhibitor(s) was not detected in serum and was reversed by adding ibuprofen. Wound fluid has a fibrinolytic inhibitor which differs from that in the circulatory system, and which may be critical to the vascular changes of burn trauma.

Immobilization of plasminogen activator, urokinase, on nylon.

Urokinase (UK), a fibrinolytic enzyme activator purified from human material was immobilized on nylon using different procedures. One was a modified method of immobilization of antigen or antibody initially carried out by Edelman and others in 1971 (Procedure I). The other was our newly devised method (Procedure II) (Sugitachi et al. 1976). Major specificities of the immobilized UK are as follows: 1. The UK revealed properties of a plasminogen activator and the optimum pH of the immobilized UK was between 7.2 and 7.4, these values being in good parallel with that of soluble UK. The immobilized UK maintained a stable fibrinolytic activity after long-term preservation and heat-treatment. 2. As the fibrinolytic activity of immobilized UK was found to be inhibited by the antiplasmin in human plasma, an antiplasmin inhibitor was immobilized on the nylon together with the UK. The antiplasmin activity was to some extent prevented using this procedure. 3. Nylon tubes immobilized with UK and antiplasmin inhibitor were used for thrombotic coagulation studies carried out according to the method of Chandler. Thrombus formation time (TFT) of UK-immobilized tubes was 30 min, while that of the non-treated tubes was no longer than 10 min.